As long acting preparations, various kinds of so-called enteric preparations have been investigated and practically applied, in which a usual quick-releasing preparation is coated with a so-called enteric substance on its surface whereby the preparation can stably withstand the gastric acid juice without dissolution in the stomach, then is disintegrated and dissolved, as it comes into contact with the weak-alkaline digestive fluid in the intestinal tracts.
For example, at the first step, (a) cores are spray-coated with a powdery drug, together with a variety of excipients, binders and disintegrators, as the cores are rotated or (b) a mixture of the powdery drug, a variety of excipients, disintegrators and binders is kneaded with an evaporable solvent such as alcohol and extruded out of a perforated basket into cylindrical granules.
At the next step, the quick-releasing preparation is uniformly coated, e.g., by spraying a solution of an enteric substance on its surface to give a slow-releasing (enteric) preparation.
The quick-releasing and slow-releasing granules are combined at a specific ratio to give a mixed preparation and the product is orally administered. The technique that the target concentration of an active ingredient in blood is achieved by the quick-releasing component at the early stage, while, by the slow-releasing component at the later stage, has been successfully applied to such a field as antibiotics in practice (see Japanese Patent Specification Laid-open No. 52-139713 (1977)).
The conventional techniques, however, tend to form the coated films of uneven thickness, when the solution of an enteric material is applied. Thinner film areas are first dissolved and the digestive juice comes through the parts into the preparation to allow the contents, especially the disintegrators and the excipients, to swell, resulting in disintegration of the granules and quicker release of the active ingredient included than in the other granules not yet disintegrated.
Generally, most of the quick-releasing preparations to be coated with an enteric film are porous, because they are produced by binding a powder with a binder. Thus, when the preparation is sprayed with a coating solution, the solution irregularly penetrates the inside of the preparation, resulting in uneven and excessive coating in several cases.
In case that the preparation has defects such as cracks on the coating films in addition to the uneven coating thickness, disintegration of the granules and dissolution of the contents start at an abnormally early stage and the uniform and reproducible dissolution cannot be absolutely expected.
In conventional techniques, cracking sometimes takes place after long-term storage, even in case that no crack was observed just after the preparation was produced. They are presumably caused by humid and mechanical stress.
There is another problem, in conventional techniques, that the contents migrate into the enteric coating. Generally speaking, the contents, especially the pharmaceutically active ingredients, have low molecular weight and many of them migrate into the outer enteric coating at a relatively high rate.
The migration of active ingredients depends upon the materials of the enteric coating, the compatibility and affinity between the contents and the coating film. Such phenomena cause, as a result, weakened protection of the contents from the gastric juice by the enteric coating. Especially, when the migration changes with the passage of time, it acts, as a major cause, to fluctuate the bioavailability (abbreviated to BAV hereinafter) of a long acting preparation.
Further, another problem in the conventional techniques is low disintegrability of the slow-releasing preparation. In the case that the enteric coating is dissolved by the intestinal digestive juice and the contents (namely quick-releasing preparation) are not readily but gradually dissolved from the surface into the digestive juice, BAV of high reproducibility cannot be expected, even if the dissolution behavior and disintegrability of the enteric coating itself would be improved. In other words, reproducible BAV cannot be expected in such a preparation as the rate-determining step for the absorption from the intestinal tracts into the body is not in the dissolution of the enteric coating, but in the dissolution of the contents. Consequently, as stated above, it is desirable for reproducible BAV that the whole granules are readily disintegrated in a short time by the digestive juice, once the coating has been dissolved.
Thus, the contents of the slow-releasing granules (namely quick-releasing granules) need to include a powerful disintegrator, but systematic investigation has hardly been made on such a powerful disintegrator that can be included in the contents of quick-releasing granules coated with an enteric material.
The problems remaining in the conventional techniques, in other words, the problems to be solved by the present invention, are as follows:
(a) The enteric coating is uneven in its thickness and excessive coating tends to happen. PA1 (b) The contents, especially the active ingredient, migrate out through the enteric coating, resulting in fluctuation of BAV. PA1 (c) BAV considerably fluctuates, because the preparation is not readily disintegrated in a short time by the impregnating digestive juice, after the enteric coating has been dissolved off. PA1 (d) The enteric coating has defects, for example, cracks in some cases. PA1 (1) Slow-releasing granules which are characterized by comprising quick-releasing granules which comprise, as essential components, an active ingredient, polyvinyl pyrrolidone polymer and a disintegrator, and on the surface area of which said polyvinyl pyrrolidone polymer is distributed in high concentration, and coating the quick-releasing granules with a polyacid enteric material to form a complex between the polyvinyl pyrrolidone polymer and the polyacid enteric material on the surface area, and PA1 (2) Slow-releasing granules which are characterized by comprising quick-releasing granules which comprise, as essential components, an active ingredient, polyvinyl pyrrolidone polymer and a powerful disintegrator homogeneously, and coating the quick-releasing granules with a polyacid enteric material to form a complex between the polyvinyl pyrrolidone polymer and the polyacid enteric material on the surface area. PA1 (3) Long acting mixed granules which are characterized by comprising PA1 (4) Long acting mixed granules which are characterized by comprising
Thus, the present inventors have made intense study in order to solve these problems completely and economically.